HRT and Cardioprotection: Where Do We Stand?

An Interview with Andrew M. Kaunitz, MD

The use of hormone replacement therapy (HRT) in postmenopausal women has been generating a lot of controversy lately. Recent studies have suggested that, contrary to prior assumptions, this regimen may increase the risks for a heart attack and for breast cancer. We asked Andrew M. Kaunitz, MD, a member of our advisory board, to respond to concerns about the safety of HRT--particularly with respect to cardiovascular disease.
TFP: Even though HRT is not indicated for cardiovascular disease prevention or treatment, and despite the fact that the Heart and Estrogen/Progestin Replacement Study (HERS) found no benefits in this regard, many doctors have been prescribing it in this context. Also, many women have been requesting it for this purpose. What is your assessment of the situation?

Kaunitz: In the late 1980s and early 1990s, a growing number of observational studies showed that HRT use was linked to a reduced risk of cardiovascular morbidity and, in some cases, mortality. In addition, laboratory data showed that HRT was associated with improvements in both lipid profiles and blood vessel functioning. As a result, many internists, OB/GYNs, and other primary care physicians have become convinced that this therapy could lower women's risk for developing cardiovascular disease.

By the mid-1990s, it became the standard of care for physicians to prescribe HRT specifically to reduce cardiovascular disease risk, even for women who did not have "classic" indications for HRT--prevention of osteoporosis, treatment of vasomotor symptoms, and treatment of vaginal atrophy.

TFP: To some degree, the state of being postmenopausal alone became an indication for HRT.

Kaunitz: Yes, that's probably true.

TFP: In light of emerging findings (e.g., an apparent increased risk for cardiovascular disease found among HRT-treated patients in the Women's Health Initiative [WHI] study), what would you recommend for physicians and patients now?

Kaunitz: I suggest that we look at three randomized, double-blind studies funded by the National Institutes of Health (NIH). The HERS, published in JAMA in 1998, enrolled almost 3000 women (mean age, 67 y) with known coronary artery disease (CAD). They were randomized to receive Premproª (conjugated equine estrogens/medroxyprogesterone acetate [MPA]) or placebo. No benefit of HRT was noted at the end of this 4-year study; that is, no decreased risk of coronary events occurred with HRT relative to placebo. These were the first study findings to challenge the conventional wisdom--that HRT prevents CAD progression.

When these findings were reported, many clinicians blamed the progestin component of HRT for the lack of cardiac benefits (HERS did not include an estrogen-only arm). Others suggested that progestins other than MPA, in combination with estrogen, might provide greater cardioprotection.
In March 2000, preliminary results of the Estrogen Replacement and Atherosclerosis (ERA) study were presented at the annual meeting of the American College of Cardiology. This study randomized about 300 women with angiographically proven CAD to receive estrogen replacement therapy (ERT), Prempro, or placebo. Disease progression occurred to the same extent in the three groups. Thus, another NIH-funded randomized study of women with CAD failed to show cardioprotection with hormone therapy. But, this study, unlike HERS, had an estrogen-only group, suggesting that the failure to observe cardioprotection with HRT is not exclusively the result of MPA use.

And, later in March 2000, the Data and Safety Monitoring Board assessed preliminary WHI data, and noted that women randomized to hormones (either ERT or Prempro) experienced a slight increase in the risk for a cardiovascular event. This study enrolled more than 25,000 women, most of whom were healthier than those in the first two studies; that is, most of the WHI participants did not have known cardiovascular disease, whereas those who entered the other two studies had known CAD. And, in the first 2 years of the WHI study, contrary to conventional wisdom, a slight increase in cardiovascular events in hormone users was noted. Participants are being informed of this, although the Data and Safety Monitoring Board has recommended that the study continue.

TFP: Did anyone recommend that WHI participants stop taking HRT?

Kaunitz: No. But when you compare the initial observational literature (which suggested that HRT users, relative to nonusers, experience as much as a 50% lower risk of CAD) with results from the three randomized trials--two of which were conducted on women with CAD and the third on a much larger group of basically healthy postmenopausal women--you can conclude that we should not be prescribing HRT specifically to prevent cardiovascular disease.

TFP: And yet, some people feel that it is way too soon to react to the WHI study. In a recent article in The New York Times, a prominent clinician stated that "hormone replacement therapy is one tool in the war on cardiovascular disease, and a very important one."

Kaunitz: Certainly, some physicians may feel that way, and readers should be aware of that position. I would like to go on record as stating that, given the most recent data, I do not believe that cardioprotection by itself constitutes an indication for prescribing HRT in postmenopausal women. This is my opinion. Although I have other things to say that might temper this statement, I want to state this clearly.

However, going back to basics, we should not forget that the three main indications for HRT are prevention of osteoporosis and fractures, treatment of vasomotor symptoms or hot flashes, and treatment or prevention of genital atrophy.

TFP: Given the WHI findings, some women who are taking HRT for these indications rather than for cardioprotection or CAD treatment may question whether or not they should continue.

Kaunitz: I don't think that any of these recent studies suggests that women should change their current therapy. Any increased cardiovascular risk may occur only in the first year or two of use; ongoing HRT use may not be associated with an elevated risk. And I also think that, as we look at the overall picture, including these studies, we should continue to view the combined use of estrogen and MPA in women who have a uterus as an appropriate approach to HRT.

Another important point is that none of the three randomized studies addressed the cardiovascular impact of transdermal ERT or HRT; all three studies used oral estrogen or oral estrogen/progestin versus placebo. And, we need to be open to the possibility that over the long term--for instance, over 5 to 10 years--we may indeed find that HRT prevents cardiovascular disease. These three studies are based on shorter-term treatment. That's why it's so important that the WHI study continue, so that we can gain that long-term experience and learn more about issues such as the impact of HRT on cardiovascular and breast cancer risk.

References:

Andrew M. Kaunitz, MD, is a Professor and Assistant Chair, Department of Obstetrics and Gynecology, University of Florida Health Science Center, Jacksonville.

Originally published in The Female Patient -- June, 2000

© Copyright, 2000 Quadrant Publishing, All Rights Reserved. Reprints are not allowed without the expressed written consent of Quadrant Publishing.